1 4890 121 OXIDATIVE STRESS AND HEPATIC NOX PROTEINS IN CHRONIC HEPATITIS C AND HEPATOCELLULAR CARCINOMA. HEPATOCELLULAR CARCINOMA (HCC) IS THE MOST COMMON LIVER CANCER AND A LEADING CAUSE OF CANCER-RELATED MORTALITY IN THE WORLD. HEPATITIS C VIRUS (HCV) IS A MAJOR ETIOLOGIC AGENT OF HCC. A MAJORITY OF HCV INFECTIONS LEAD TO CHRONIC INFECTION THAT CAN PROGRESS TO CIRRHOSIS AND, EVENTUALLY, HCC AND LIVER FAILURE. A COMMON PATHOGENIC FEATURE PRESENT IN HCV INFECTION, AND OTHER CONDITIONS LEADING TO HCC, IS OXIDATIVE STRESS. HCV DIRECTLY INCREASES SUPEROXIDE AND H2O2 FORMATION IN HEPATOCYTES BY ELEVATING NOX PROTEIN EXPRESSION AND SENSITIZING MITOCHONDRIA TO REACTIVE OXYGEN SPECIES GENERATION WHILE DECREASING GLUTATHIONE. NITRIC OXIDE SYNTHESIS AND HEPATIC IRON ARE ALSO ELEVATED. FURTHERMORE, ACTIVATION OF PHAGOCYTIC NADPH OXIDASE (NOX) 2 OF HOST IMMUNE CELLS IS LIKELY TO EXACERBATE OXIDATIVE STRESS IN HCV-INFECTED PATIENTS. KEY MECHANISMS OF HCC INCLUDE GENOME INSTABILITY, EPIGENETIC REGULATION, INFLAMMATION WITH CHRONIC TISSUE INJURY AND SUSTAINED CELL PROLIFERATION, AND MODULATION OF CELL GROWTH AND DEATH. OXIDATIVE STRESS, OR NOX PROTEINS, PLAYS VARIOUS ROLES IN THESE MECHANISMS. NOX PROTEINS ALSO FUNCTION IN HEPATIC FIBROSIS, WHICH COMMONLY PRECEDES HCC, AND NOX4 ELEVATION BY HCV IS MEDIATED BY TRANSFORMING GROWTH FACTOR BETA. THIS REVIEW SUMMARIZES MECHANISMS OF ONCOGENESIS BY HCV, HIGHLIGHTING THE ROLES OF OXIDATIVE STRESS AND HEPATIC NOX ENZYMES IN HCC. 2014 2 199 29 ACTIVATED HISTONE ACETYLTRANSFERASE P300/CBP-RELATED SIGNALLING PATHWAYS MEDIATE UP-REGULATION OF NADPH OXIDASE, INFLAMMATION, AND FIBROSIS IN DIABETIC KIDNEY. ACCUMULATING EVIDENCE IMPLICATES THE HISTONE ACETYLATION-BASED EPIGENETIC MECHANISMS IN THE PATHOETIOLOGY OF DIABETES-ASSOCIATED MICRO-/MACROVASCULAR COMPLICATIONS. DIABETIC KIDNEY DISEASE (DKD) IS A PROGRESSIVE CHRONIC INFLAMMATORY MICROVASCULAR DISORDER ULTIMATELY LEADING TO GLOMERULOSCLEROSIS AND KIDNEY FAILURE. WE HYPOTHESIZED THAT HISTONE ACETYLTRANSFERASE P300/CBP MAY BE INVOLVED IN MEDIATING DIABETES-ACCELERATED RENAL DAMAGE. IN THIS STUDY, WE AIMED AT INVESTIGATING THE POTENTIAL ROLE OF P300/CBP IN THE UP-REGULATION OF RENAL NADPH OXIDASE (NOX), REACTIVE OXYGEN SPECIES (ROS) PRODUCTION, INFLAMMATION, AND FIBROSIS IN DIABETIC MICE. DIABETIC C57BL/6J MICE WERE RANDOMIZED TO RECEIVE 10 MG/KG C646, A SELECTIVE P300/CBP INHIBITOR, OR ITS VEHICLE FOR 4 WEEKS. WE FOUND THAT IN THE KIDNEY OF C646-TREATED DIABETIC MICE, THE LEVEL OF H3K27AC, AN EPIGENETIC MARK OF ACTIVE GENE EXPRESSION, WAS SIGNIFICANTLY REDUCED. PHARMACOLOGICAL INHIBITION OF P300/CBP SIGNIFICANTLY DOWN-REGULATED THE DIABETES-INDUCED ENHANCED EXPRESSION OF NOX SUBTYPES, PRO-INFLAMMATORY, AND PRO-FIBROTIC MOLECULES IN THE KIDNEY OF MICE, AND THE GLOMERULAR ROS OVERPRODUCTION. OUR STUDY PROVIDES EVIDENCE THAT THE ACTIVATION OF P300/CBP ENHANCES ROS PRODUCTION, POTENTIALLY GENERATED BY UP-REGULATED NOX, INFLAMMATION, AND THE PRODUCTION OF EXTRACELLULAR MATRIX PROTEINS IN THE DIABETIC KIDNEY. THE DATA SUGGEST THAT P300/CBP-PHARMACOLOGICAL INHIBITORS MAY BE ATTRACTIVE TOOLS TO MODULATE DIABETES-ASSOCIATED PATHOLOGICAL PROCESSES TO EFFICIENTLY REDUCE THE BURDEN OF DKD. 2021 3 3378 29 HIV INDUCED NITRIC OXIDE AND LIPID PEROXIDATION, INFLUENCES NEONATAL BIRTHWEIGHT IN A SOUTH AFRICAN POPULATION. HIV HAS BEEN IMPLICATED IN ADVERSE BIRTH OUTCOMES, DUE TO INCREASED OXIDATIVE STRESS AND INFLAMMATION. IN ADDITION, HIV HAS BEEN REPORTED TO INCREASE NITRIC OXIDE LEVELS. THEREFORE THE COMBINED EXPOSURES TO HIV AND TRAFFIC-RELATED AIR POLLUTION, WITHIN SOUTH DURBAN, SOUTH AFRICA (SA), MAY LEAD TO ADVERSE BIRTH OUTCOMES. HOWEVER, THE EXACT MECHANISM IS STILL UNKNOWN; THIS STUDY AIMED TO IDENTIFY A POTENTIAL MECHANISM. FIRST, THE INFLUENCE OF HIV ON OXIDATIVE AND NITROSATIVE STRESS MARKERS IN PREGNANT WOMEN WAS ASSESSED. SECONDLY, THE EFFECT OF THESE STRESS MAKERS AND EXPOSURE TO OXIDES OF NITROGEN (NOX) ON NEONATAL BIRTHWEIGHT (BW) WAS EVALUATED. FINALLY, THE EFFECT HIV AND TRAFFIC-RELATED POLLUTION EXPOSURE HAS ON THE OXIDATIVE AND ENDOPLASMIC PROFILE AND EPIGENETIC REGULATION OF NRF2-KEAP1 PATHWAY BY MIR-144 AND MIR-28 IN PREGNANT WOMEN WAS DETERMINED. WOMEN, IN THEIR THIRD TRIMESTER WITH SINGLETON PREGNANCIES, WHO WERE HIV+ AND HIV-, WERE RECRUITED FROM DURBAN, SA. BIOMARKER LEVELS OF SERUM NITRITES/NITRATES (NO) AND MALONDIALDEHYDE (MDA) WERE ANALYSED AND MRNA EXPRESSION LEVELS OF OXIDATIVE AND ENDOPLASMIC STRESS RESPONSE GENES WERE ASSESSED. LAND REGRESSION MODELLING WAS PERFORMED TO DETERMINE NOX EXPOSURE LEVELS. HIV EXPOSURE DURING PREGNANCY WAS ASSOCIATED WITH INCREASED NO LEVELS. NO WAS SHOWN TO REDUCE NEONATAL BW. NO AND MDA WAS FOUND TO RECIPROCALLY INCREASE EACH OTHER, WITH HIV DIFFERENTIALLY INFLUENCING MDA'S EFFECT ON BW. HIV DOWN-REGULATED MIR-144 WHICH WAS NEGATIVELY ASSOCIATED WITH NRF2, SUGGESTING A POTENTIAL MECHANISM FOR HIV ASSOCIATED CHRONIC OXIDATIVE STRESS. THIS STUDY PROPOSES THAT NO PLAYS A KEY ROLE IN NEONATAL BW REDUCTION IN RESPONSE TO HIV AND TRAFFIC-RELATED AIR POLLUTION. 2018 4 6456 31 THYMOSIN BETA4 PREVENTS OXIDATIVE STRESS, INFLAMMATION, AND FIBROSIS IN ETHANOL- AND LPS-INDUCED LIVER INJURY IN MICE. THYMOSIN BETA 4 (TBETA4), AN ACTIN-SEQUESTERING PROTEIN, IS INVOLVED IN TISSUE DEVELOPMENT AND REGENERATION. IT PREVENTS INFLAMMATION AND FIBROSIS IN SEVERAL TISSUES. WE INVESTIGATED THE ROLE OF TBETA4 IN CHRONIC ETHANOL- AND ACUTE LIPOPOLYSACCHARIDE- (LPS-) INDUCED MOUSE LIVER INJURY. C57BL/6 MICE WERE FED 5% ETHANOL IN LIQUID DIET FOR 4 WEEKS PLUS BINGE ETHANOL (5 G/KG, GAVAGE) WITH OR WITHOUT LPS (2 MG/KG, INTRAPERITONEAL) FOR 6 HOURS. TBETA4 (1 MG/KG, INTRAPERITONEAL) WAS ADMINISTERED FOR 1 WEEK. WE DEMONSTRATED THAT TBETA4 PREVENTED ETHANOL- AND LPS-MEDIATED INCREASE IN LIVER INJURY MARKERS AS WELL AS CHANGES IN LIVER PATHOLOGY. IT ALSO PREVENTED ETHANOL- AND LPS-MEDIATED INCREASE IN OXIDATIVE STRESS BY DECREASING ROS AND LIPID PEROXIDATION AND INCREASING THE ANTIOXIDANTS, REDUCED GLUTATHIONE AND MANGANESE-DEPENDENT SUPEROXIDE DISMUTASE. IT ALSO PREVENTED THE ACTIVATION OF NUCLEAR FACTOR KAPPA B BY BLOCKING THE PHOSPHORYLATION OF THE INHIBITORY PROTEIN, IKAPPAB, THEREBY PREVENTED PROINFLAMMATORY CYTOKINE PRODUCTION. MOREOVER, TBETA4 PREVENTED FIBROGENESIS BY SUPPRESSING THE EPIGENETIC REPRESSOR, METHYL-CPG-BINDING PROTEIN 2, THAT COORDINATELY REVERSED THE EXPRESSION OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA AND DOWNREGULATED FIBROGENIC GENES, PLATELET-DERIVED GROWTH FACTOR-BETA RECEPTOR, ALPHA-SMOOTH MUSCLE ACTIN, COLLAGEN 1, AND FIBRONECTIN, RESULTING IN REDUCED FIBROSIS. OUR DATA SUGGEST THAT TBETA4 HAS ANTIOXIDANT, ANTI-INFLAMMATORY, AND ANTIFIBROTIC POTENTIAL DURING ALCOHOLIC LIVER INJURY. 2018 5 1330 39 DEPRESSIVE-LIKE BEHAVIORS ARE REGULATED BY NOX1/NADPH OXIDASE BY REDOX MODIFICATION OF NMDA RECEPTOR 1. INVOLVEMENT OF REACTIVE OXYGEN SPECIES (ROS) HAS BEEN SUGGESTED IN THE DEVELOPMENT OF PSYCHIATRIC DISORDERS. NOX1 IS A NONPHAGOCYTIC FORM OF NADPH OXIDASE WHOSE EXPRESSION IN THE NERVOUS SYSTEM IS NEGLIGIBLE COMPARED WITH OTHER NOX ISOFORMS. HOWEVER, NOX1-DERIVED ROS INCREASE INFLAMMATORY PAIN AND TOLERANCE TO OPIOID ANALGESIA. TO CLARIFY THE ROLE OF NOX1 IN THE BRAIN, WE EXAMINED DEPRESSIVE-LIKE BEHAVIORS IN MICE DEFICIENT IN NOX1 (NOX1(-/Y)). DEPRESSIVE-LIKE BEHAVIORS INDUCED BY CHRONIC SOCIAL DEFEAT STRESS OR ADMINISTRATION OF CORTICOSTERONE (CORT) WERE SIGNIFICANTLY AMELIORATED IN NOX1(-/Y) GENERATION OF ROS WAS SIGNIFICANTLY ELEVATED IN THE PREFRONTAL CORTEX (PFC) OF MICE ADMINISTRATED WITH CORT, WHILE NOX1 MRNA WAS UPREGULATED ONLY IN THE VENTRAL TEGMENTAL AREA (VTA) AMONG BRAIN AREAS RESPONSIBLE FOR EMOTIONAL BEHAVIORS. DELIVERY OF MIRNA AGAINST NOX1 TO VTA RESTORED CORT-INDUCED DEPRESSIVE-LIKE BEHAVIORS IN WILD-TYPE (WT) LITTERMATES. ADMINISTRATION OF CORT TO WT, BUT NOT TO NOX1(-/Y), SIGNIFICANTLY REDUCED TRANSCRIPT LEVELS OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF), WITH A CONCOMITANT INCREASE IN DNA METHYLATION OF THE PROMOTER REGIONS IN BDNF DELIVERY OF MIRNA AGAINST NOX1 TO VTA RESTORED THE LEVEL OF BDNF MRNA IN WT PFC. REDOX PROTEOME ANALYSES DEMONSTRATED THAT NMDA RECEPTOR 1 (NR1) WAS AMONG THE MOLECULES REDOX REGULATED BY NOX1. IN CULTURED CORTICAL NEURONS, HYDROGEN PEROXIDE SIGNIFICANTLY SUPPRESSED NMDA-INDUCED UPREGULATION OF BDNF TRANSCRIPTS IN NR1-EXPRESSING CELLS BUT NOT IN CELLS HARBORING MUTANT NR1 (C744A). TOGETHER, THESE FINDINGS SUGGEST A KEY ROLE OF NOX1 IN DEPRESSIVE-LIKE BEHAVIORS THROUGH NR1-MEDIATED EPIGENETIC MODIFICATION OF BDNF IN THE MESOPREFRONTAL PROJECTION.SIGNIFICANCE STATEMENT NADPH OXIDASE IS A SOURCE OF REACTIVE OXYGEN SPECIES (ROS) THAT HAVE BEEN IMPLICATED IN THE PATHOGENESIS OF VARIOUS NEUROLOGICAL DISORDERS. WE PRESENTLY SHOWED THE INVOLVEMENT OF A NONPHAGOCYTIC TYPE OF NADPH OXIDASE, NOX1, IN MAJOR DEPRESSIVE DISORDERS, INCLUDING BEHAVIORAL, BIOCHEMICAL, AND ANATOMICAL CHANGES IN MICE. THE OXIDATION OF NR1 BY NOX1-DERIVED ROS WAS DEMONSTRATED IN PREFRONTAL CORTEX (PFC), WHICH MAY BE CAUSALLY LINKED TO THE DOWNREGULATION OF BDNF, PROMOTING DEPRESSIVE-LIKE BEHAVIORS. GIVEN THAT NOX1 IS UPREGULATED ONLY IN VTA BUT NOT IN PFC, MESOCORTICAL PROJECTIONS APPEAR TO PLAY A CRUCIAL ROLE IN NOX1-DEPENDENT DEPRESSIVE-LIKE BEHAVIORS. OUR STUDY IS THE FIRST TO PRESENT THE POTENTIAL MOLECULAR MECHANISM UNDERLYING THE DEVELOPMENT OF MAJOR DEPRESSION THROUGH THE NOX1-INDUCED OXIDATION OF NR1 AND EPIGENETIC MODIFICATION OF BDNF. 2017 6 2181 31 EPIGENETIC MECHANISMS REGULATE NADPH OXIDASE-4 EXPRESSION IN CELLULAR SENESCENCE. AGING IS A WELL-KNOWN RISK FACTOR FOR A LARGE NUMBER OF CHRONIC DISEASES, INCLUDING THOSE OF THE LUNG. CELLULAR SENESCENCE IS ONE OF THE HALLMARKS OF AGING, AND CONTRIBUTES TO THE PATHOGENESIS OF AGE-RELATED DISEASES. RECENT STUDIES IMPLICATE THE REACTIVE OXYGEN SPECIES (ROS)-GENERATING ENZYME, NADPH OXIDASE 4 (NOX4) IN CELLULAR SENESCENCE. IN THIS STUDY, WE INVESTIGATED POTENTIAL MECHANISMS FOR EPIGENETIC REGULATION OF NOX4. WE OBSERVED CONSTITUTIVELY HIGH LEVELS OF NOX4 GENE/PROTEIN AND ACTIVITY IN A MODEL OF REPLICATION-INDUCED CELLULAR SENESCENCE OF LUNG FIBROBLASTS. IN REPLICATIVE SENESCENT FIBROBLASTS, THE NOX4 GENE IS ENRICHED WITH THE ACTIVATION HISTONE MARK, H4K16AC, AND INVERSELY ASSOCIATED WITH THE REPRESSIVE HISTONE MARK, H4K20ME3, SUPPORTING AN ACTIVE TRANSCRIPTIONAL CHROMATIN CONFORMATION. SILENCING OF THE HISTONE ACETYLTRANSFERASE MOF, WHICH SPECIFICALLY ACETYLATES H4K16, DOWN-REGULATES NOX4 GENE/PROTEIN EXPRESSION. THE NOX4 GENE PROMOTER IS RICH IN CPG SITES; MIXED COPIES OF METHYLATED AND UNMETHYLATED NOX4 DNA WERE DETECTED IN BOTH NONSENESCENT AND SENESCENT CELLS. INTERESTINGLY, THE NOX4 GENE IS VARIABLY ASSOCIATED WITH SPECIFIC DNA METHYLTRANSFERASES AND METHYL BINDING PROTEINS IN THESE TWO CELL POPULATIONS. THESE RESULTS INDICATE A CRITICAL ROLE FOR HISTONE MODIFICATIONS INVOLVING H4K16AC IN EPIGENETIC ACTIVATION OF THE NOX4 GENE, WHILE THE ROLE OF DNA METHYLATION MAY BE CONTEXTUAL. DEFINING MECHANISMS FOR THE EPIGENETIC REGULATION OF NOX4 WILL AID IN THE DEVELOPMENT OF NOVEL THERAPEUTIC STRATEGIES FOR AGE-RELATED DISEASES IN WHICH THIS GENE IS OVEREXPRESSED, IN PARTICULAR IDIOPATHIC PULMONARY FIBROSIS AND CANCER. 2015 7 2202 29 EPIGENETIC MODIFICATION OF MIR-10A REGULATES RENAL DAMAGE BY TARGETING CREB1 IN TYPE 2 DIABETES MELLITUS. EMERGING EVIDENCE HAS SHOWN THAT MICRORNA-MEDIATED GENE EXPRESSION MODULATION PLAYS A CRUCIAL ROLE IN THE PATHOGENESIS OF TYPE 2 DIABETES MELLITUS, BUT THE NOVEL MIRNAS INVOLVED IN TYPE 2 DIABETES AND ITS FUNCTIONAL REGULATORY MECHANISMS STILL NEED TO BE DETERMINED. IN THIS STUDY, WE ASSESSED THE ROLE OF MIR-10A IN EXTRACELLULAR MATRIX ACCUMULATION IN THE KIDNEY OF DIABETIC MELLITUS INDUCED BY COMBINING ADMINISTRATION OF CHRONIC HIGH FAT DIET (HFD) AND LOW DOSAGE OF STREPTOZOTOCIN (STZ, 35MG/KG). HERE, WE FOUND THAT HFD/STZ ADMINISTRATION DECREASED THE LEVEL OF MICRORNA (MIR-10A) EXPRESSION IN ICR STRAIN MICE. OVEREXPRESSION OF MIR-10A ALLEVIATED THE INCREASED RATIO OF URINE ALBUMIN-TO-CREATININE (ACR) RATIO OF HFD/STZ MICE. IN CONTRAST, KNOCKDOWN OF MIR-10A INCREASED THE RATIO OF KIDNEY ACR IN NAIVE MICE. FURTHERMORE, CAMP RESPONSE ELEMENT BINDING PROTEIN 1 (CREB1) WAS VALIDATED AS A TARGET OF MIR-10A IN VITRO AND IN VIVO. CREB1 AND ITS DOWNSTREAM FIBRONECTIN (FN, EXTRACELLULAR MATRIX) WERE INCREASED IN HFD/STZ-TREATED MICE, WHICH WAS REVERSED BY KIDNEY MIR-10A OVEREXPRESSION. THE CONTENT OF CREB1 AND FN WAS INCREASED BY MIR-10A KNOCKDOWN IN KIDNEY OF NAIVE MICE. FURTHERMORE, HISTONE DEACETYLASE 3 (HDAC3) WAS REVEALED TO BE INCREASED IN KIDNEY OF HFD/STZ MICE, ACCOMPANIED WITH THE AUGMENTATION OF ACR RATIO AND FN LEVEL. KNOCKDOWN OF HDAC3 WITH SIRNA SIGNIFICANTLY CAUSED THE INCREASE OF MIR-10A, RESULTING IN THE DECREASE IN CREB1 AND FN EXPRESSION IN KIDNEY OF HFD/STZ MICE. CONTRARILY, HDAC3 OVEREXPRESSION MEDIATED BY LENTIVIRUS DECREASED MIR-10A CONTENT, AND ENHANCED ACR VALUE, CREB1 AND FN FORMATION IN NAIVE MICE. COLLECTIVELY, THESE RESULTS ELUCIDATE THAT HDAC3/MIR-10A/CREB1 SERVES AS A NEW MECHANISM UNDERLYING KIDNEY INJURY, PROVIDING POTENTIAL THERAPEUTIC TARGETS IN TYPE 2 DIABETES. 2016 8 449 26 APOCYNIN PREVENTS ANXIETY-LIKE BEHAVIOR AND HISTONE DEACETYLASES OVEREXPRESSION INDUCED BY SUB-CHRONIC STRESS IN MICE. ANXIETY DISORDERS ARE COMMON MENTAL HEALTH DISEASES AFFECTING UP TO 7% OF PEOPLE AROUND THE WORLD. STRESS IS CONSIDERED ONE OF THE MAJOR ENVIRONMENTAL RISK FACTORS TO PROMOTE ANXIETY DISORDERS THROUGH MECHANISMS INVOLVING EPIGENETIC CHANGES. MOREOVER, ALTERATION IN REDOX BALANCE AND INCREASED REACTIVE OXYGEN SPECIES (ROS) PRODUCTION HAVE BEEN DETECTED IN ANXIETY PATIENTS AND IN STRESSED-ANIMAL MODELS OF ANXIETY. HERE WE TESTED IF THE ADMINISTRATION OF APOCYNIN, A NATURAL ORIGIN ANTIOXIDANT, MAY PREVENT THE ANXIETY-LIKE PHENOTYPE AND REDUCTION OF HISTONE ACETYLATION INDUCED BY A SUBCHRONIC FORCED SWIMMING STRESS (FSS) PARADIGM. WE FOUND THAT APOCYNIN PREVENTED THE ENHANCED LATENCY TIME IN THE NOVELTY-SUPPRESSED FEEDING TEST, AND THE PRODUCTION OF MALONDIALDEHYDE INDUCED BY FSS. MOREOVER, APOCYNIN WAS ABLE TO BLOCK THE UPREGULATION OF P47PHOX, A KEY SUBUNIT OF THE NADPH OXIDASE COMPLEX. FINALLY, APOCYNIN PREVENTED THE RISE OF HIPPOCAMPAL HDAC1, HDAC4 AND HDAC5, AND THE REDUCTION OF HISTONE-3 ACETYLATION LEVELS PROMOTED BY FSS EXPOSURE. IN CONCLUSION, OUR RESULTS PROVIDE EVIDENCE THAT APOCYNIN REDUCES THE DELETERIOUS EFFECT OF STRESS AND SUGGESTS THAT OXIDATIVE STRESS MAY REGULATE EPIGENETIC MECHANISMS. 2021 9 868 24 CHRONIC ADVANCED-GLYCATION END PRODUCTS TREATMENT INDUCES TXNIP EXPRESSION AND EPIGENETIC CHANGES IN GLOMERULAR PODOCYTES IN VIVO AND IN VITRO. ADVANCED GLYCATION END PRODUCTS (AGES) PLAY AN IMPORTANT ROLE IN OXIDATIVE STRESS AND INFLAMMATION, PROCESSES IMPLICATED IN THE DEVELOPMENT AND PROGRESSION OF KIDNEY DYSFUNCTION. IN THE PRESENT STUDY, WE INVESTIGATED THE PARTICIPATION OF THE PRO-OXIDANT PROTEIN THIOREDOXIN-INTERACTING PROTEIN (TXNIP) AND OF EPIGENETIC MECHANISMS ON KIDNEY TISSUE (IN VIVO, IN NON-DIABETIC RATS) AND ON TERMINALLY DIFFERENTIATED GLOMERULAR PODOCYTES (IN VITRO) CHRONICALLY EXPOSED TO AGES. AGES INDUCED TOTAL KIDNEY AND GLOMERULAR TXNIP EXPRESSION AND DECREASED H3K27ME3 CONTENT. CONCOMITANT TREATMENT WITH THE ANTIOXIDANT N-ACETYL-CYSTEINE (NAC) REVERSED ONLY THE INCREASED TXNIP EXPRESSION. TXNIP EXPRESSION POSITIVELY CORRELATED WITH PROTEINURIA AND NEGATIVELY CORRELATED WITH H3K27ME3 CONTENT. IN VITRO STUDIES IN PODOCYTES SHOWED THAT 72 H EXPOSURE TO AGES DECREASED NEPHRIN EXPRESSION AND INCREASED TXNIP, NOX4, COL4A1, AND EPITHELIAL-TO-MESENCHYMAL TRANSITION (EMT) MARKERS (ACTA2, SNAIL1, AND TGFB1). PODOCYTES TREATMENT WITH NAC REVERSED NOX4, COL4A1, ACTA2, AND TGFB1 INCREASED EXPRESSION BUT DID NOT ABROGATE THE REDUCED EXPRESSION OF NEPHRIN. MIR-29A EXPRESSION WAS DOWNREGULATED BY AGES IN VIVO, BUT NOT IN VITRO. IN CONCLUSION, TREATMENT OF NON-DIABETIC RATS WITH AGES INDUCED TXNIP EXPRESSION AND DECREASED THE CONTENTS OF THE REPRESSIVE EPIGENETIC MARK H3K27ME3 AND OF MIR-29A, POTENTIALLY DRIVING INJURY TO GLOMERULAR FILTRATION BARRIER AND PODOCYTES DYSFUNCTION. 2021 10 3242 35 HEPATIC NCOR1 DELETION EXACERBATES ALCOHOL-INDUCED LIVER INJURY IN MICE BY PROMOTING CCL2-MEDIATED MONOCYTE-DERIVED MACROPHAGE INFILTRATION. NUCLEAR RECEPTOR COREPRESSOR 1 (NCOR1) IS A COREPRESSOR OF THE EPIGENETIC REGULATION OF GENE TRANSCRIPTION THAT HAS IMPORTANT FUNCTIONS IN METABOLISM AND INFLAMMATION, BUT LITTLE IS KNOWN ABOUT ITS ROLE IN ALCOHOL-ASSOCIATED LIVER DISEASE (ALD). IN THIS STUDY, WE DEVELOPED MICE WITH HEPATOCYTE-SPECIFIC NCOR1 KNOCKOUT (NCOR1(HEP-/-)) USING THE ALBUMIN-CRE/LOXP SYSTEM AND INVESTIGATED THE ROLE OF NCOR1 IN THE PATHOGENESIS OF ALD AND THE UNDERLYING MECHANISMS. THE TRADITIONAL ALCOHOL FEEDING MODEL AND NIAAA MODEL OF ALD WERE BOTH ESTABLISHED IN WILD-TYPE AND NCOR1(HEP-/-) MICE. WE SHOWED THAT AFTER ALD WAS ESTABLISHED, NCOR1(HEP-/-) MICE HAD WORSE LIVER INJURY BUT LESS STEATOSIS THAN WILD-TYPE MICE. WE DEMONSTRATED THAT HEPATOCYTE-SPECIFIC LOSS OF NCOR1 ATTENUATED LIVER STEATOSIS BY PROMOTING FATTY ACID OXIDATION BY UPREGULATING BMAL1 (A CIRCADIAN CLOCK COMPONENT THAT HAS BEEN REPORTED TO PROMOTE PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA (PPARALPHA)-MEDIATED FATTY BETA-OXIDATION BY UPREGULATING DE NOVO LIPID SYNTHESIS). ON THE OTHER HAND, HEPATOCYTE-SPECIFIC LOSS OF NCOR1 EXACERBATED ALCOHOL-INDUCED LIVER INFLAMMATION AND OXIDATIVE STRESS BY RECRUITING MONOCYTE-DERIVED MACROPHAGES VIA C-C MOTIF CHEMOKINE LIGAND 2 (CCL2). IN THE MOUSE HEPATOCYTE LINE AML12, NCOR1 KNOCKDOWN SIGNIFICANTLY INCREASED ETHANOL-INDUCED CCL2 RELEASE. THESE RESULTS SUGGEST THAT HEPATOCYTE NCOR1 PLAYS DISTINCT ROLES IN CONTROLLING LIVER INFLAMMATION AND STEATOSIS, WHICH PROVIDES NEW INSIGHTS INTO THE DEVELOPMENT OF TREATMENTS FOR STEATOHEPATITIS INDUCED BY CHRONIC ALCOHOL CONSUMPTION. 2022 11 4906 26 P300 EXERTS AN EPIGENETIC ROLE IN CHRONIC NEUROPATHIC PAIN THROUGH ITS ACETYLTRANSFERASE ACTIVITY IN RATS FOLLOWING CHRONIC CONSTRICTION INJURY (CCI). BACKGROUND: NEUROPATHIC PAIN IS DETRIMENTAL TO HUMAN HEALTH; HOWEVER, ITS PATHOGENESIS STILL REMAINS LARGELY UNKNOWN. OVEREXPRESSION OF PAIN-ASSOCIATED GENES AND INCREASED NOCICEPTIVE SOMATO-SENSITIVITY ARE WELL OBSERVED IN NEUROPATHIC PAIN. THE IMPORTANCE OF EPIGENETIC MECHANISMS IN REGULATING THE EXPRESSION OF PRO- OR ANTI-NOCICEPTIVE GENES HAS BEEN REVEALED BY STUDIES RECENTLY, AND WE HYPOTHESIZE THAT THE TRANSCRIPTIONAL COACTIVATOR AND THE HISTONE ACETYLTRANSFERASE E1A BINDING PROTEIN P300 (P300), AS A PART OF THE EPIGENETIC MECHANISMS OF GENE REGULATION, MAY BE INVOLVED IN THE PATHOGENESIS OF NEUROPATHIC PAIN INDUCED BY CHRONIC CONSTRICTION INJURY (CCI). TO TEST THIS HYPOTHESIS, TWO DIFFERENT APPROACHES WERE USED IN THIS STUDY: (I) DOWN-REGULATING P300 WITH SPECIFIC SMALL HAIRPIN RNA (SHRNA) AND (II) CHEMICAL INHIBITION OF P300 ACETYLTRANSFERASE ACTIVITY BY A SMALL MOLECULE INHIBITOR, C646. RESULTS: USING THE CCI RAT MODEL, WE FOUND THAT THE P300 EXPRESSION WAS INCREASED IN THE LUMBAR SPINAL CORD ON DAY 14 AFTER CCI. THE TREATMENT WITH INTRATHECAL P300 SHRNA REVERSED CCI-INDUCED MECHANICAL ALLODYNIA AND THERMAL HYPERALGESIA, AND SUPPRESSED THE EXPRESSION OF CYCLOOXYGENASE-2 (COX-2), A NEUROPATHIC PAIN-ASSOCIATED FACTOR. FURTHERMORE, C646, AN INHIBITOR OF P300 ACETYLTRANSFERASE, ALSO ATTENUATED MECHANICAL ALLODYNIA AND THERMAL HYPERALGESIA, ACCOMPANIED BY A SUPPRESSED COX-2 EXPRESSION, IN THE SPINAL CORD. CONCLUSIONS: THE RESULTS SUGGEST THAT, THROUGH ITS ACETYLTRANSFERASE ACTIVITY IN THE SPINAL CORD AFTER CCI, P300 EPIGENETICALLY PLAYS AN IMPORTANT ROLE IN NEUROPATHIC PAIN. INHIBITING P300, USING INTERFERING RNA OR C646, MAY BE A PROMISING APPROACH TO THE DEVELOPMENT OF NEW NEUROPATHIC PAIN THERAPIES. 2012 12 5860 28 SULFORAPHANE PREVENTS ANGIOTENSIN II-INDUCED CARDIOMYOPATHY BY ACTIVATION OF NRF2 THROUGH EPIGENETIC MODIFICATION. NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR (NRF2) IS AN IMPORTANT REGULATOR OF CELLULAR ANTIOXIDANT DEFENCE. WE PREVIOUSLY SHOWED THAT SFN PREVENTED ANG II-INDUCED CARDIAC DAMAGE VIA ACTIVATION OF NRF2. HOWEVER, THE UNDERLYING MECHANISM OF SFN'S PERSISTENT CARDIAC PROTECTION REMAINS UNCLEAR. THIS STUDY AIMED TO EXPLORE THE POTENTIAL OF SFN IN ACTIVATING CARDIAC NRF2 THROUGH EPIGENETIC MECHANISMS. WILD-TYPE MICE WERE INJECTED SUBCUTANEOUSLY WITH ANG II, WITH OR WITHOUT SFN. ADMINISTRATION OF CHRONIC ANG II-INDUCED CARDIAC INFLAMMATORY FACTOR EXPRESSION, OXIDATIVE DAMAGE, FIBROSIS AND CARDIAC REMODELLING AND DYSFUNCTION, ALL OF WHICH WERE EFFECTIVELY IMPROVED BY SFN TREATMENT, COUPLED WITH AN UP-REGULATION OF NRF2 AND DOWNSTREAM GENES. BISULFITE GENOME SEQUENCING AND CHROMATIN IMMUNOPRECIPITATION (CHIP) WERE PERFORMED TO DETECT THE METHYLATION LEVEL OF THE FIRST 15 CPGS AND HISTONE H3 ACETYLATION (AC-H3) STATUS IN THE NRF2 PROMOTER REGION, RESPECTIVELY. THE RESULTS SHOWED THAT SFN REDUCED ANG II-INDUCED CPG HYPERMETHYLATION AND PROMOTED AC-H3 ACCUMULATION IN THE NRF2 PROMOTER REGION, ACCOMPANIED BY THE INHIBITION OF GLOBAL DNMT AND HDAC ACTIVITY, AND A DECREASED PROTEIN EXPRESSION OF KEY DNMT AND HDAC ENZYMES. TAKEN TOGETHER, SFN EXERTS ITS CARDIOPROTECTIVE EFFECT THROUGH EPIGENETIC MODIFICATION OF NRF2, WHICH MAY PARTIALLY CONTRIBUTE TO LONG-TERM ACTIVATION OF CARDIAC NRF2. 2021 13 4366 19 MIRNA-23A/CXCR4 REGULATES NEUROPATHIC PAIN VIA DIRECTLY TARGETING TXNIP/NLRP3 INFLAMMASOME AXIS. BACKGROUND: CHEMOKINE CXC RECEPTOR 4 (CXCR4) IN SPINAL GLIAL CELLS HAS BEEN IMPLICATED IN NEUROPATHIC PAIN. HOWEVER, THE REGULATORY CASCADES OF CXCR4 IN NEUROPATHIC PAIN REMAIN ELUSIVE. HERE, WE INVESTIGATED THE FUNCTIONAL REGULATORY ROLE OF MIRNAS IN THE PAIN PROCESS AND ITS INTERPLAY WITH CXCR4 AND ITS DOWNSTREAM SIGNALING. METHODS: MIRNAS AND CXCR4 AND ITS DOWNSTREAM SIGNALING MOLECULES WERE MEASURED IN THE SPINAL CORDS OF MICE WITH SCIATIC NERVE INJURY VIA PARTIAL SCIATIC NERVE LIGATION (PSNL). IMMUNOBLOTTING, IMMUNOFLUORESCENCE, IMMUNOPRECIPITATION, AND MAMMAL TWO-HYBRID AND BEHAVIORAL TESTS WERE USED TO EXPLORE THE DOWNSTREAM CXCR4-DEPENDENT SIGNALING PATHWAY. RESULTS: CXCR4 EXPRESSION INCREASED IN SPINAL GLIAL CELLS OF MICE WITH PSNL-INDUCED NEUROPATHIC PAIN. BLOCKING CXCR4 ALLEVIATED THE PAIN BEHAVIOR; CONTRARILY, OVEREXPRESSING CXCR4 INDUCED PAIN HYPERSENSITIVITY. MICRORNA-23A-3P (MIR-23A) DIRECTLY BOUNDS TO 3' UTR OF CXCR4 MRNA. PSNL-INDUCED NEUROPATHIC PAIN SIGNIFICANTLY REDUCED MRNA EXPRESSION OF MIR-23A. OVEREXPRESSION OF MIR-23A BY INTRATHECAL INJECTION OF MIR-23A MIMICS OR LENTIVIRUS REDUCED SPINAL CXCR4 AND PREVENTED PSNL-INDUCED NEUROPATHIC PAIN. IN CONTRAST, KNOCKDOWN OF MIR-23A BY INTRATHECAL INJECTION OF MIR-23A INHIBITOR OR LENTIVIRUS INDUCED PAIN-LIKE BEHAVIOR, WHICH WAS REDUCED BY CXCR4 INHIBITION. ADDITIONALLY, MIR-23A KNOCKDOWN OR CXCR4 OVEREXPRESSION IN NAIVE MICE COULD INCREASE THE THIOREDOXIN-INTERACTING PROTEIN (TXNIP), WHICH WAS ASSOCIATED WITH INDUCTION OF NOD-LIKE RECEPTOR PROTEIN 3 (NLRP3) INFLAMMASOME. INDEED, CXCR4 AND TXNIP WERE CO-EXPRESSED. THE MAMMAL TWO-HYBRID ASSAY REVEALED THE DIRECT INTERACTION BETWEEN CXCR4 AND TXNIP, WHICH WAS INCREASED IN THE SPINAL CORD OF PSNL MICE. IN PARTICULAR, INHIBITION OF TXNIP REVERSED PAIN BEHAVIOR ELICITED BY PSNL, MIR-23A KNOCKDOWN, OR CXCR4 OVEREXPRESSION. MOREOVER, MIR-23A OVEREXPRESSION OR CXCR4 KNOCKDOWN INHIBITED THE INCREASE OF TXNIP AND NLRP3 INFLAMMASOME IN PSNL MICE. CONCLUSIONS: MIR-23A, BY DIRECTLY TARGETING CXCR4, REGULATES NEUROPATHIC PAIN VIA TXNIP/NLRP3 INFLAMMASOME AXIS IN SPINAL GLIAL CELLS. EPIGENETIC INTERVENTIONS AGAINST MIR-23A, CXCR4, OR TXNIP MAY POTENTIALLY SERVE AS NOVEL THERAPEUTIC AVENUES IN TREATING PERIPHERAL NERVE INJURY-INDUCED NOCICEPTIVE HYPERSENSITIVITY. 2018 14 294 25 AGING INCREASES VULNERABILITY TO STRESS-INDUCED DEPRESSION VIA UPREGULATION OF NADPH OXIDASE IN MICE. BRAIN AGING PROCEEDS WITH CELLULAR AND MOLECULAR CHANGES IN THE LIMBIC SYSTEM. AGING-DEPENDENT CHANGES MIGHT AFFECT EMOTION AND STRESS COPING, YET THE UNDERLYING MECHANISMS REMAIN UNCLEAR. HERE, WE SHOW AGED (18-MONTH-OLD) MICE EXHIBIT UPREGULATION OF NADPH OXIDASE AND OXIDATIVE STRESS IN THE HIPPOCAMPUS, WHICH MIRRORS THE CHANGES IN YOUNG (2-MONTH-OLD) MICE SUBJECTED TO CHRONIC STRESS. AGED MICE THAT LACK P47PHOX, A KEY SUBUNIT OF NADPH OXIDASE, DO NOT SHOW INCREASED OXIDATIVE STRESS. AGED MICE EXHIBIT DEPRESSION-LIKE BEHAVIOR FOLLOWING WEAK STRESS THAT DOES NOT PRODUCE DEPRESSIVE BEHAVIOR IN YOUNG MICE. AGED MICE HAVE REDUCED EXPRESSION OF THE EPIGENETIC FACTOR SUV39H1 AND ITS UPSTREAM REGULATOR P-AMPK, AND INCREASED EXPRESSION OF PPP2CA IN THE HIPPOCAMPUS-CHANGES THAT OCCUR IN YOUNG MICE EXPOSED TO CHRONIC STRESS. SUV39H1 MEDIATES STRESS- AND AGING-INDUCED SUSTAINED UPREGULATION OF P47PHOX AND OXIDATIVE STRESS. THESE RESULTS SUGGEST THAT AGING INCREASES SUSCEPTIBILITY TO STRESS BY UPREGULATING NADPH OXIDASE IN THE HIPPOCAMPUS. 2020 15 3940 35 LNCRNA DLEU2 REGULATES SIRTUINS AND MITOCHONDRIAL RESPIRATORY CHAIN COMPLEX IV: A NOVEL PATHWAY IN OBESITY AND OFFSPRING'S HEALTH. BACKGROUND: LONG NON-CODING RNAS (LNCRNAS) HAVE EMERGED AS A RAPIDLY EXPANDING AREA OF INTEREST IN CHRONIC DISEASES. THEY ARE MOSTLY UNKNOWN FOR ROLES IN METABOLIC REGULATION. SIRTUINS, AN EPIGENETIC MODULATOR CLASS, REGULATE METABOLIC PATHWAYS. HOWEVER, HOW SIRTUINS ARE REGULATED VIA LNCRNA IS UNKNOWN. WE HYPOTHESIZED THAT A HIGH-FAT HIGH-FRUCTOSE DIET (HFD-HF) DURING PREGNANCY WOULD INCREASE THE RISK FOR OBESITY VIA LNCRNA-SIRTUIN PATHWAYS. METHODS: FEMALE C57BL/6 MICE (F0) WERE FED EITHER CHOW DIET (CD) OR HFD-HF FOR 6 WEEKS TILL BIRTH. THE PUPS (F1) WERE FED EITHER CD OR HFD-HF FOR 20 WEEKS. EXPRESSION OF DLEU2, SIRTUINS, MITOCHONDRIAL RESPIRATORY COMPLEXES, AND OXIDATIVE STRESS WERE INVESTIGATED IN THE F1 LIVERS. FASTING BLOOD GLUCOSE, INSULIN SENSITIVITY, GLUCOSE TOLERANCE, BODY AND TISSUES WEIGHT WERE MEASURED. A MECHANISTIC INTERACTION WAS THEN CARRIED OUT USING A DLEU2 KNOCKDOWN EXPERIMENT IN THE HEPG2 CELL. RESULTS: DLEU2 AND SIRTUINS WERE BOTH SIGNIFICANTLY DECREASED IN THE LIVERS OF HFD-HF FED MALE F1 WHOSE MOTHERS WERE EITHER FED CD OR HFD-HF DURING REPRODUCTIVE AND PREGNANCY WINDOWS. CONFIRMING THIS CONNECTION, UPON SILENCING DLEU2, TRANSCRIPTION LEVELS OF SIRT1 THROUGH 6 AND TRANSLATIONAL LEVELS OF SIRT1, 3, 5, AND 6 WERE SIGNIFICANTLY DOWNREGULATED. KNOCKDOWN OF DLEU2 SIGNIFICANTLY DECREASED THE PROTEIN LEVEL OF CYTOCHROME-C OXIDASE (COMPLEX IV, MTCO1) WITHOUT ALTERING OTHER MITOCHONDRIAL COMPLEXES, DECREASED MITOCHONDRIAL MEMBRANE POTENTIAL, DECREASED ATP, AND INCREASED REACTIVE OXYGEN SPECIES. INTERESTINGLY, IN F1 LIVERS, THE PROTEIN LEVEL OF MTCO1 WAS ALSO SIGNIFICANTLY DECREASED UNDER AN HFD-HF DIET OR EVEN UNDER CHOW DIET IF THE MOTHER WAS EXPOSED TO HFD-HF. CONCLUSION: OUR FINDINGS REVEAL FOR THE FIRST TIME THAT ONE LNCRNA CAN REGULATE SIRTUINS AND A SPECIFIC MITOCHONDRIAL COMPLEX. FURTHERMORE, DIET OR MATERNAL DIET CAN MODULATE DLEU2 AND ITS DOWNSTREAM REGULATORS IN OFFSPRING, SUGGESTING A POTENTIAL ROLE OF DLEU2 IN METABOLIC DISORDERS OVER ONE OR MORE GENERATIONS. 2022 16 6215 26 THE INVOLVEMENT OF ADAR1 IN ANTIDEPRESSANT ACTION BY REGULATING BDNF VIA MIR-432. BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) IS A BIOMARKER OF DEPRESSION. RECENT STUDIES HAVE FOUND ADENOSINE DEAMINASE ACTING ON RNA1 (ADAR1) IS A NOVEL TARGET BEING SENSITIVE TO STRESS AT EPIGENETIC LEVEL. THE EPIGENETIC REGULATION MECHANISM OF STRESS-RELATED DEPRESSION IS STILL UNCLEAR SO FAR. TO EXPLORE THE POTENTIAL REGULATING MECHANISM OF ADAR1 ON BDNF, OVER AND LOW EXPRESSION OF ADAR1 IN PC12 AND SH-SY5Y CELL LINES ARE PREPARED. IN THE MEANWHILE, CHRONIC UNPREDICTABLE STRESS (CUS) MICE ARE TREATED WITH ADAR1 INDUCER (INTERFERON-GAMMA, IFN-GAMMA). ADAR1 REGULATES BDNF EXPRESSION, WHICH IS PROVEN BY THAT OVER AND LOW EXPRESSIONS OF ADAR1 INCREASE AND DECREASE BDNF MRNA AND PROTEIN RESPECTIVELY IN VITRO. ADDITIONALLY, ADAR1 INDUCER ALLEVIATES THE DEPRESSIVE-LIKE BEHAVIOR OF CUS MICE BY RECOVERING THE DECREASED BDNF PROTEIN IN BRAIN AND SERUM. MOREOVER, OVER AND LOW EXPRESSIONS OF ADAR1 REDUCE AND ENHANCE MICRORNA-432 (MIR-432) EXPRESSION RESPECTIVELY IN VITRO. FURTHERLY, OVER AND LOW MIR-432 EXPRESSIONS LEAD TO DECREASED AND INCREASED BDNF AND ADAR1 MRNA, PROTEIN AND IMMUNOREACTIVITY RESPECTIVELY IN VITRO. THE ABOVE RESULTS DEMONSTRATE THAT ADAR1 IS INVOLVED IN ANTIDEPRESSANT ACTION BY REGULATING BDNF VIA MIR-432. THOSE NOVEL FINDINGS CAN PROVIDE A NEW IDEA FOR THE STUDY OF EPIGENETIC REGULATION MECHANISM, EARLY DIAGNOSIS, AND EFFECTIVE TREATMENT OF STRESS-RELATED DEPRESSION. 2021 17 4747 31 NOVEL MODULATORS OF HEPATOSTEATOSIS, INFLAMMATION AND FIBROGENESIS. ALCOHOLIC STEATOSIS, INSTEAD OF BEING INNOCUOUS, PLAYS A CRITICAL ROLE IN LIVER INFLAMMATION AND FIBROGENESIS. THE SEVERITY OF FATTY LIVER IS GOVERNED BY THE CONCERTED BALANCE BETWEEN LIPID TRANSPORT, SYNTHESIS, AND DEGRADATION. WHEREAS SCAVENGER RECEPTOR CLASS B, TYPE I (SR-B1) IS CRITICAL FOR REVERSE CHOLESTEROL UPTAKE BY THE LIVER, PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA (PPARGAMMA) COACTIVATOR-1ALPHA AND -BETA (PGC1ALPHA AND PGC1BETA) ARE CRITICAL FOR LIPID DEGRADATION AND SYNTHESIS, RESPECTIVELY. BECAUSE BETAINE IS A LIPOTROPIC AGENT, WE HAVE EVALUATED ITS EFFECTS ON ALCOHOLIC STEATOSIS. BETAINE EFFECTIVELY PREVENTED CHRONIC ALCOHOL-MEDIATED (I) IMPAIRED SR-B1 GLYCOSYLATION, PLASMA MEMBRANE LOCALIZATION, AND CONSEQUENT IMPAIRED CHOLESTEROL TRANSPORT; AND (II) UP REGULATION OF PGC-1BETA, STEROL REGULATORY ELEMENT-BINDING PROTEIN 1C AND DOWNSTREAM LIPOGENIC GENES WITH CONCOMITANT INCREASED LIVER CHOLESTEROL, TRIGLYCERIDES AND HEPATIC LIPID SCORE. SIMILARLY, BECAUSE OF ITS ANTI-INFLAMMATORY AND ANTI-FIBROTIC EFFECTS IN OTHER ORGANS, WE EVALUATED THE PROTECTIVE EFFECTS OF THYMOSIN BETA4 (TBETA4) AGAINST CARBON TETRACHLORIDE (CCL4)-INDUCED HEPATOTOXICITY IN RAT. TBETA4 PREVENTED CCL4-INDUCED (I) NECROSIS, INFLAMMATORY INFILTRATION AND UP-REGULATION OF ALPHA1(2)COLLAGEN, ALPHA-SMOOTH MUSCLE ACTIN (ALPHA-SMA), PLATELET DERIVED GROWTH FACTOR BETA (PDGF-BETA) RECEPTOR AND FIBRONECTIN MRNA EXPRESSION; (II) DOWN-REGULATION OF ADIPOGENIC GENE, PPARGAMMA AND THE UP-REGULATION OF EPIGENETIC REPRESSOR GENE, METHYL CPG BINDING PROTEIN 2 (MECP2) MRNA LEVELS, SUGGESTING THAT THE ANTI-FIBROGENIC ACTIONS OF TBETA4 INVOLVE THE PREVENTION OF TRANS-DIFFERENTIATION OF QUIESCENT HEPATIC STELLATE CELLS INTO MYO-FIBROBLASTS LARGELY BY UP-REGULATING PPARGAMMA AND BY DOWN-REGULATING MECP2 GENES. WE THEREFORE CONCLUDE THAT BETAINE AND TBETA4 CAN EFFECTIVELY PROTECT AGAINST ALCOHOLIC HEPATOSTEATOSIS AND HEPATIC FIBROGENESIS, RESPECTIVELY. 2014 18 4354 27 MIR-21-5P DIRECTLY CONTRIBUTES TO REGULATING ENOS EXPRESSION IN HUMAN ARTERY ENDOTHELIAL CELLS UNDER NORMOXIA AND HYPOXIA. CLINICAL CONDITIONS ASSOCIATED WITH HYPOXIA AND OXIDATIVE STRESS, SUCH AS FETAL GROWTH RESTRICTION (FGR), RESULTS IN ENDOTHELIAL DYSFUNCTION. PREVIOUS REPORTS SHOW THAT CHANGES IN ENOS EXPRESSION UNDER THESE CONDITIONS ARE TIGHTLY CONTROLLED BY DNA METHYLATION AND HISTONE POSTTRANSLATIONAL MODIFICATIONS. HOWEVER, THE CONTRIBUTION OF AN ORCHESTRATING EPIGENETIC MECHANISM, SUCH AS MIRNAS, ON THE NO-RELATED GENES EXPRESSION HAS NOT BEEN ADDRESSED. WE AIMED TO DETERMINE THE LEVELS OF MIRNAS HIGHLY EXPRESSED IN NORMAL ENDOTHELIAL CELLS (EC), MIR-21 AND MIR-126, IN FGR HUMAN UMBILICAL ARTERY EC (HUAEC), AND THEIR EFFECTS ON HYPOXIA-DEPENDENT REGULATION OF BOTH, NO-RELATED AND OXIDATIVE STRESS-RELATED GENES. RESULTS WERE VALIDATED BY TRANSCRIPTOME ANALYSIS OF HUAEC CULTURED UNDER CHRONIC LOW OXYGEN CONDITIONS. CULTURED FGR-HUAEC SHOWED DECREASED HSA-MIR-21, DDAH1, SOD1, AND NRF2, BUT INCREASED MIR-126, NOX4, AND ENOS LEVELS, COMPARED WITH CONTROLS. MIR-21-5P LEVELS IN FGR WERE ASSOCIATED WITH INCREASED HG-MIR-21 GENE PROMOTER METHYLATION, WITH NO CHANGES IN HG-MIR-126 GENE PROMOTER METHYLATION. HUAEC EXPOSED TO HYPOXIA SHOWED A TRANSIENT INCREASE IN ENOS AND DDAH11, PARALLELED BY DECREASE MIR-21-5P LEVELS, BUT NO CHANGES IN MIR-126-3P AND THE OTHER GENES UNDER STUDY. TRANSCRIPTOME PROFILING SHOWED AN INVERSE RELATIONSHIP AMONG MIR-21 AND SEVERAL TRANSCRIPTS TARGETED BY MIR-21 IN HUAEC EXPOSED TO HYPOXIA, MEANWHILE MIR-21-5P-MIMIC DECREASED ENOS AND DDAH1 TRANSCRIPTS STABILITY, BLOCKING THEIR INDUCTION BY HYPOXIA. CONSEQUENTLY, FGR PROGRAMS A HYPOXIA-RELATED MIRNA THAT CONTRIBUTES TO THE REGULATION OF THE NO PATHWAY, INVOLVING A DIRECT EFFECT OF MIR-21-5P ON ENOS TRANSCRIPT STABILITY, NOT PREVIOUSLY REPORTED. MOREOVER, HYPOXIA DOWNREGULATES MIR-21-5P, CONTRIBUTING TO INCREASING THE EXPRESSION OF NO-RELATED GENES IN ARTERIAL ENDOTHELIAL CELLS. 2020 19 4603 27 NEGATIVE ALLOSTERIC MODULATION OF MGLUR5 PARTIALLY CORRECTS PATHOPHYSIOLOGY IN A MOUSE MODEL OF RETT SYNDROME. RETT SYNDROME (RTT) IS CAUSED BY MUTATIONS IN THE GENE ENCODING METHYL-CPG BINDING PROTEIN 2 (MECP2), AN EPIGENETIC REGULATOR OF MRNA TRANSCRIPTION. HERE, WE REPORT A TEST OF THE HYPOTHESIS OF SHARED PATHOPHYSIOLOGY OF RTT AND FRAGILE X, ANOTHER MONOGENIC CAUSE OF AUTISM AND INTELLECTUAL DISABILITY. IN FRAGILE X, THE LOSS OF THE MRNA TRANSLATIONAL REPRESSOR FMRP LEADS TO EXAGGERATED PROTEIN SYNTHESIS DOWNSTREAM OF METABOTROPIC GLUTAMATE RECEPTOR 5 (MGLUR5). WE FOUND THAT MGLUR5- AND PROTEIN-SYNTHESIS-DEPENDENT SYNAPTIC PLASTICITY WERE SIMILARLY ALTERED IN AREA CA1 OF MECP2 KO MICE. CA1 PYRAMIDAL CELL-TYPE-SPECIFIC, GENOME-WIDE PROFILING OF RIBOSOME-BOUND MRNAS WAS PERFORMED IN WILD-TYPE AND MECP2 KO HIPPOCAMPAL CA1 NEURONS TO REVEAL THE MECP2-REGULATED "TRANSLATOME." WE FOUND SIGNIFICANT OVERLAP BETWEEN RIBOSOME-BOUND TRANSCRIPTS OVEREXPRESSED IN THE MECP2 KO AND FMRP MRNA TARGETS. THESE TENDED TO ENCODE LONG GENES THAT WERE FUNCTIONALLY RELATED TO EITHER CYTOSKELETON ORGANIZATION OR THE DEVELOPMENT OF NEURONAL CONNECTIVITY. IN THE FMR1 KO MOUSE, CHRONIC TREATMENT WITH MGLUR5-NEGATIVE ALLOSTERIC MODULATORS (NAMS) HAS BEEN SHOWN TO AMELIORATE MANY MUTANT PHENOTYPES BY CORRECTING EXCESSIVE PROTEIN SYNTHESIS. IN MECP2 KO MICE, WE FOUND THAT MGLUR5 NAM TREATMENT SIGNIFICANTLY REDUCED THE LEVEL OF OVEREXPRESSED RIBOSOME-ASSOCIATED TRANSCRIPTS, PARTICULARLY THOSE THAT WERE ALSO FMRP TARGETS. SOME RETT PHENOTYPES WERE ALSO AMELIORATED BY TREATMENT, MOST NOTABLY HIPPOCAMPAL CELL SIZE AND LIFESPAN. TOGETHER, THESE RESULTS SUGGEST A POTENTIAL MECHANISTIC LINK BETWEEN MECP2-MEDIATED TRANSCRIPTION REGULATION AND MGLUR5/FMRP-MEDIATED PROTEIN TRANSLATION REGULATION THROUGH COREGULATION OF A SUBSET OF GENES RELEVANT TO SYNAPTIC FUNCTIONS. SIGNIFICANCE STATEMENT: ALTERED REGULATION OF SYNAPTIC PROTEIN SYNTHESIS HAS BEEN HYPOTHESIZED TO CONTRIBUTE TO THE PATHOPHYSIOLOGY THAT UNDERLIES MULTIPLE FORMS OF INTELLECTUAL DISABILITY AND AUTISM SPECTRUM DISORDER. HERE, WE SHOW IN A MOUSE MODEL OF RETT SYNDROME (MECP2 KO) THAT METABOTROPIC GLUTAMATE RECEPTOR 5 (MGLUR5)- AND PROTEIN-SYNTHESIS-DEPENDENT SYNAPTIC PLASTICITY ARE ABNORMAL IN THE HIPPOCAMPUS. WE FOUND THAT A SUBSET OF RIBOSOME-BOUND MRNAS WAS ABERRANTLY UPREGULATED IN HIPPOCAMPAL CA1 NEURONS OF MECP2 KO MICE, THAT THESE SIGNIFICANTLY OVERLAPPED WITH FMRP DIRECT TARGETS AND/OR SFARI HUMAN AUTISM GENES, AND THAT CHRONIC TREATMENT OF MECP2 KO MICE WITH AN MGLUR5-NEGATIVE ALLOSTERIC MODULATOR TUNES DOWN UPREGULATED RIBOSOME-BOUND MRNAS AND PARTIALLY IMPROVES MUTANT MICE PHENOTYPES. 2016 20 1667 28 DOWNREGULATION OF PCAF BY MIR-181A/B PROVIDES FEEDBACK REGULATION TO TNF-ALPHA-INDUCED TRANSCRIPTION OF PROINFLAMMATORY GENES IN LIVER EPITHELIAL CELLS. ABERRANT CELLULAR RESPONSES TO PROINFLAMMATORY CYTOKINES, SUCH AS TNF-ALPHA, ARE PATHOGENIC FEATURES IN MOST CHRONIC INFLAMMATORY DISEASES. A VARIETY OF EXTRACELLULAR AND INTRACELLULAR FEEDBACK PATHWAYS HAS EVOLVED TO PREVENT AN INAPPROPRIATE CELLULAR REACTION TO THESE PROINFLAMMATORY CYTOKINES. IN THIS STUDY, WE REPORT THAT TNF-ALPHA TREATMENT OF HUMAN AND MOUSE CHOLANGIOCYTES AND HEPATOCYTES DOWNREGULATED EXPRESSION OF P300/CBP-ASSOCIATED FACTOR (PCAF), A COACTIVATOR AND AN ACETYLTRANSFERASE THAT PROMOTES HISTONE ACETYLATION AND GENE TRANSCRIPTION. OF THESE UPREGULATED MICRORNAS IN TNF-ALPHA-TREATED CELLS, MIR-181A/B (MIR-181A AND MIR-181B) SUPPRESSED TRANSLATION OF PCAF MRNA. FUNCTIONAL MANIPULATION OF MIR-181A/B CAUSED RECIPROCAL ALTERATIONS IN PCAF PROTEIN EXPRESSION IN CULTURED CHOLANGIOCYTES AND HEPATOCYTES. INHIBITION OF MIR-181A/B FUNCTION WITH ANTI-MIRS BLOCKED TNF-ALPHA-INDUCED SUPPRESSION OF PCAF EXPRESSION. PROMOTER RECRUITMENT OF PCAF WAS SHOWN TO BE ASSOCIATED WITH TNF-ALPHA-INDUCED TRANSCRIPTION OF INFLAMMATORY GENES. INTRIGUINGLY, PRETREATMENT OF CELLS WITH TNF-ALPHA INHIBITED TRANSCRIPTION OF INFLAMMATORY GENES IN RESPONSE TO SUBSEQUENT TNF-ALPHA STIMULATION. OVEREXPRESSION OF PCAF OR INHIBITION OF MIR-181A/B FUNCTION WITH ANTI-MIRS ATTENUATED THE INHIBITORY EFFECTS OF TNF-ALPHA PRETREATMENT ON EPITHELIAL INFLAMMATORY RESPONSE TO SUBSEQUENT TNF-ALPHA STIMULATION. DOWNREGULATION OF PCAF AND THE INHIBITORY EFFECTS OF TNF-ALPHA PRETREATMENT ON LIVER EPITHELIAL INFLAMMATORY RESPONSE WERE FURTHER CONFIRMED IN A MOUSE MODEL OF TNF-ALPHA I.P. INJECTION. THESE DATA SUGGEST THAT PCAF IS A TARGET FOR MIR-181A/B, AND DOWNREGULATION OF PCAF BY TNF-ALPHA PROVIDES NEGATIVE FEEDBACK REGULATION TO INFLAMMATORY REACTIONS IN LIVER EPITHELIAL CELLS, A PROCESS THAT MAY BE RELEVANT TO THE EPIGENETIC FINE-TUNING OF EPITHELIAL INFLAMMATORY PROCESSES IN GENERAL. 2012